The simple phospholipid, lysophosphatidic acid (LPA) is an autacoid that, like prostaglandins and adenosine, can be generated by many cell types and binds to a family of G-protein coupled receptors (LPA1, LPA2 and LPA3). LPA has heterogeneous functional effects including cellular proliferation, alterations in differentiation, cell survival, suppression of apoptosis and platelet aggregation. In addition to these effects, LPA is similar to other inflammatory lipid mediators (platelet activating factor, prostaglandins, thromboxane) and has the capacity to evoke an immune response by attracting and activating immune cells and regulating leukocyte endothelial cell interaction. These multiple divergent responses are likely mediated by specific LPA receptors that have distinct signaling mechanisms. The high concentration of LPC in plasma and serum suggests that local production of LPA could evoke an injury response that may play a significant role in ischemia-reperfusion injury (IRI). This is supported by our preliminary data that indicate that, VPC12249, a selective LPA1/LPA3 antagonist markedly reduces IR injury >70% in mouse kidneys. The dramatic response by this compound underscores the critical role that LPA receptors play in renal tubule cell survival and injury. Thus we hypothesize that renal ischemia reperfusion induces locally an increase in LPA levels that mediates heterogeneous effects; LPA2 activation mediates cells survival and LPA3 activation mediates tissue injury. Aim 1 tests the hypothesis that a selective LPA3 antagonism mediates protection from IR. Aim 2 tests the hypothesis that Nudeotide Pyrophosphatase/Phosphodiesterase (NPP) family regulates renal LPA levels locally during renal IR injury. Aim 3 tests the hypothesis that LPA3 mediates tissue injury through bone marrow (BM) and non-BM derived ceils. Aim 4 tests the hypothesis that proximal tubule (PT) LPA3 receptor blockade and LPA2 activation mediates tissue protection. This proposal combines expertise in the LPA synthetic chemistry program of Drs. Timothy Macdonald (Professor, Department of Chemistry, UVA) and Kevin R. Lynch (Professor, Department of Pharmacology, UVA) that will provide incisive molecular and pharmacological reagents in studies that are designed to define the specific effects of LPA receptor subtypes and the mechanisms of protection by selective blockade of LPA receptors. Furthermore, these studies will provide the foundation for future human clinical trials of acute renal failure and renal allograft preservation.